This invention relates to a series of compounds which are peptidyl heterocyclic ketone inflammatory cell serine protease inhibitors and their compositions and methods for the prevention and treatment of a variety of immunomediated inflammatory disorders, skin hyperpigmentation, and trypsin mediated disorders. More particularly, these compounds are potent and selective inhibitors of tryptase and are therefore effective for the prevention and treatment of inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis, as well as other immunomediated inflammatory disorders, such as rheumatoid arthritis, conjunctivitis, psoriasis, inflammatory bowel disease, various vascular and dermatological conditions.
Mast cells are a key cellular component of the inflammatory response and when activated, secrete numerous proinflammatory mediators, including histamine, arachidonic acid derivatives, and some serine proteases. Among these mast cell serine proteases is a unique carboxypeptidase, chymase and tryptase (Walls et al. Eur. J. Pharmacol. 1997, 328, 89-97). Active tryptase is a structurally unique trypsin-like serine protease which exists as a tetramer that is stabilized by heparin proteoglycans which are stored and secreted with the enzyme (Bode et al. Nature 1998, 392, 306-311). With the exception of neutrophil lactoferrin and possibly secretory leukocyte proteinase inhibitor, tryptase is generally not affected by endogenous serine protease inhibitors such as xcex12-macroglobin, xcex12-proteinase inhibitor, aprotinin, and antithrombin. It is postulated that in vivo tryptase activity may be regulated by the dissociation of the active tryptase tetramer into inactive monomers via the removal of heparin.
Tryptase is secreted exclusively by mast cells and comprises up to 25% of the total protein of the mast cell (Schwartz et al., J. Clin. Invest. 1989, 84, 1188-1195). Consequently, mast cell-derived tryptase is secreted in high concentrations at sites of tissue injury. Activated mast cells in atherosclerotic/restenotic plaque have been implicated in plaque rupture and stenosis and are also manifested in inflamed tissues of the gastrointestinal tract. Elevated tryptase levels have been detected in bronchoalveolar lavage fluid (asthma), tears (conjunctivitis), blister fluids (dermatitis), blood (anaphylaxis), cerebrospinal fluid (multiple sclerosis), synovial fluid (rheumatoid arthritis) (Rice et al. Curr. Pharm. Design. 1998, 4, 381-396). Elevated levels of tryptase have also been found in diseased arteries (atherosclerotic, restenotic) relative to normal arteries. Some cigarette smokers have elevated bronchooalveolar lavage fluid tryptase levels relative to nonsmokers, providing support for the hypothesis that mast cell proteases may contribute to lung destruction in smoker""s emphysema (Kalenderian et al. Chest 1998, 94, 119-123).
The potent bronchodilating neuropeptides, vasoactive intestinal peptide (VIP) and peptide histidine methionine (PHM) are readily cleaved by tryptase in vitro whereas substance P, a potent bronchoconstricting peptide, is not (Drazen et al. J. Clin. Invest 1993, 91, 235-243). Tryptase has demonstrated the ability to generate bradykinin, which is known to induce bronchoconstriction in asthmatics (Zhang et al. Mediators of Inflammation. 1997, 6, 311-317). The ability of tryptase to stimulate inflammatory eosinophils and neutophil chemotaxis in vitro and in vivo is well known (Walls et al. J. Immunol. 1997, 159, 6216-6225). Inhaled tryptase has been shown to cause bronchoconstriction in sheep through the release of histamine (Abraham et al. Amer. J. of Respir. and Crit. Care Med. 1996, 154, 649-654). Its ability to directly stimulate mast cell degranulation in vitro and in animal models suggests that there may be a tryptase mediated amplification mechanism of the allergic inflammatory response (Walls et al. Eur. J. Pharmacol. 1997, 328, 89-97).
Currently, only trypsin and tryptase are known to activate the protease-activated receptor 2 (PAR-2), a cell surface G-protein-coupled receptor. The activation of PAR-2 is primarily associated with the induction of mitogenic response indicating that tryptase may have a role in pathological conditions associated with tissue hyperplasia, including the airway hyperplasia found in chronic asthmatics (Stone et al. FEBS Letters 1997, 417, 267-269). Tryptase also has multiple effects on fibroblasts and there is in vitro evidence to suggest that tryptase may involved in the early stages of fibrotic diseases, such as fibrotic lung disease, schieroderma, atherosclerosis, and cardiomyopathic disorders (Marone et al. Circulation 1998, 97, 971-978). Hence, an inhibitor of tryptase could provide a novel therapeutic approach for the prevention and treatment of a variety inflammatory diseases, such as vascular injury (atherosclerosis, restenosis), arthritis, inflammatory bowel disease, Crohn""s disease, dermatitis, urticaria, bullous pemphigoid, psoriasis, schleroderma, fibrosis, conjunctivitis, allergic rhinitis, and particularly asthma.
Asthma is the most common chronic disease in developed countries. It is a complex disease involving multiple biochemical mediators for both its acute and chronic manifestations. Asthma is frequently characterized by the progressive development of hyperresponsiveness of the trachea and bronchi to both immunospecific allergens as well as generalized chemical or physical stimuli. The hyperresponsiveness of asthmatic bronchiolar tissue is postulated to result from chronic inflammation reactions, which irritate and damage the epithelium lining the airway wall and promote pathological thickening of the underlying tissue. Bronchial biopsy studies have indicated that even patients with mild asthma have features of inflammation in the airway wall. Mast cells have long been implicated in the pathogenesis of asthma, particularly in the acute response immediately after the exposure to allergen (Zhang et al. Mediators of Inflammation 1997, 6, 311-317).
The therapeutic strategy of employing tryptase inhibitors as a treatment for asthma in humans has been recently validated by the selective tryptase inhibitor, APC-366 (Tanaka et al. Am. J. Respir. Crit. Care Med. 1995, 152, 2076-2083). A recent Phase Ila study was conducted with 16 mild asthmatics who were dosed with either placebo or a nebulized dry powder formulation of APC-366 (Rice et al. Curr. Pharm. Design. 1998, 4, 381-396). Compared with placebo, the same subjects had a statistically significant improvement for the late airway response (33%; xcfx81=0.012) and a mean maximum decrease of forced expiratory volume in one second (21%; xcfx81=0.007) for late airway hyperresponsiveness. These positive results demonstrate that tryptase inhibition is a promising approach for the treatment of asthma in humans. 
Currently, the most effect therapy for chronic asthma involves treatment with glucocorticoids (Barnes New Engl. J. Med. 1995, 332, 868-875). However, glucocorticoid administration also generates a litany of local and systemic side-effects. Because of the limitations of glucocorticoids, there is an unmet medical need for improved asthma therapy. In contrast to drugs such as steroids that elicit multiple actions, tryptase inhibitors may elicit fewer side-effects through the selective inhibition of a specific inflammatory mediator (tryptase) that is exclusive to mast cells. Hence, tryptase inhibitors may offer similar efficacy in the treatment of asthma as the glucocorticoids without the same undesirable systemic side-effects.
Skin coloring has been of concern to human beings for many years. In particular, the ability to remove hyperpigmentation, such as found in age spots, freckles or aging skin generally, is of interest to individuals desiring a uniform complexion. There are also hyperpigmentation disorders that are desirable to treat. The compounds of the formula (I) have been shown to be effective in causing skin depigmentation. The compounds of the formula (I) have been shown to be effective in causing skin depigmentation and therefore may be useful in the treatment and/or prevention of skin hyperpigmentation.
Yet another use for the compounds of this invention is as trypsin inhibitors. Inhibitors of trypsin have been used clinically in the treatment of certain disorders, such as pancreatitis. The IC50 values for the compounds of the invention compare favorably with the pancreatic agents camostat mesilate and nafamostat (IC50 s, 1xc3x9710xe2x88x928 and 1.3xc3x9710xe2x88x928 respectively). The compounds of formula (I) may be used in the same manner as those therapeutic agents.
The compounds of the formula (I) also function as inhibitors of thrombin and factor Xa. Consequently, they may be useful for the treatment of thrombin and/or factor Xa mediated disorders, such as thrombosis.
The invention relates to novel compounds of the Formula (I): 
wherein:
A is
selected from the group consisting of substituted C3-8 cycloalkylcarbonyl (where the substituents on the C3-8 cycloalkyl group are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyl, C1-4alkylcarbonylamino or C1-4alkoxycarbonyl), substituted norbornanecarbonyl (where the substituents on the norbomane group are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyl, C1-4alkylcarbonylamino or C1-4alkoxycarbonyl), substituted norbornenecarbonyl (where the substituents on the norbornene group are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyl, C1-4alkylcarbonylamino or C1-4alkoxycarbonyl), substituted adamantanecarbonyl (where the substituents on the adamantane group are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyl, C1-4alkylcarbonylamino or C1-4alkoxycarbonyl), substituted arylcarbonyl (where the substituents on the aryl group are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyl, C1-4alkylcarbonylamino or C1-4alkoxycarbonyl), heteroarylcarbonyl, substituted heteroarylcarbonyl (where the the substituents on the heteroaryl are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, or C1-4alkoxycarbonyl), pyridylcarbonyl, substituted pyridylcarbonyl (where the substituents on the pyridine ring are independently one to three substituents selected from C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyl, C1-4alkylcarbonylamino or C1-4alkoxycarbonyl), pyrrolocarbonyl, substituted pyrrolocarbonyl (where the substituents on the pyridine ring are independently one to three substituents selected from C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyl, C1-4alkylcarbonylamino or C1-4alkoxycarbonyl), amidoC1-5alkylcarbonyl, 
xe2x80x83a D or L amino acid which is coupled at its carboxy terminus to the nitrogen depicted in formula (I) and is selected from the group consisting of alanine, 2-azetidinecarboxylic acid, glycine, pyrrole-2-carboxylic acid, dehydroproline, proline, substituted proline (where the the substituents on the proline are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, oxo, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyloxy, phenylalkyloxy, phenyl or C1-4alkoxycarbonyl), pipecolinic acid, substituted pipecolinic acid (where the the substituents on the piperidine of the pipecolinic acid group are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, oxo, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyloxy, phenylalkyloxy, phenyl or C1-4alkoxycarbonyl), valine, norleucine, leucine, tert-leucine, isoleucine, sarcosine, asparagine, serine, methionine, threonine, phenylalanine, 1-naphthalanine, 2-naphthalanine, 2-thienylalanine, 3-thienylalanine, [1,2,3,4]-tetrahydroisoquinoline-1-carboxylic acid and [1,2,3,4]-tetrahydroisoquinoline-2-carboxylic acid,
where the amino terminus of said amino acid is connected to a member selected from the group consisting of [1,2,3,4]-tetrahydroisoquinoline-1-carbonyl, [1,2,3,4]-tetrahydroisoquinoline-3-carbonyl, formyl, C1-4alkoxycarbonyl, C1-4alkylcarbonyl, perfluoroC1-4alkylsulfonyl, C1-4alkylsulfonyl, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, sulfonamido, arylsulfonyl, substituted arylsulfonyl (where the aryl substituents are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, or C1-4alkoxycarbonyl), camphorsulfonyl, C1-4alkylsulfinyl, arylsulfinyl, substituted arylsulfinyl (where the aryl substituents are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, or C1-4alkoxycarbonyl), and arylcarbonyl; or
a poly peptide comprised of two amino acids,
where the first amino acid is a D or L amino acid, bound via its carboxy terminus to the nitrogen depicted in formula (I) and is selected from the group consisting of proline and substituted proline (where the the substituents on the proline are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, oxo, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyloxy, aralkyloxy, aryl or C1-4alkoxycarbonyl),
and the second D or L amino acid, is bound to the amino terminus of said first amino acid, and is selected from the group consisting of aspartic acid , aspartic acid-4-C1-4alkyl ester, glutamic acid, glutamic acid-5-C1-4alkyl ester, serine, phenylalanine, substituted phenylalanine (where the phenyl substituents are independently selected from one or more of, C1-4alkyl, perfluoroC1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy or C1-4alkoxycarbonyl), cyclohexylglycine, and cyclohexylalanine,
where the amino terminus of said second amino acid is monosubstituted with a member of the group consisting of C1-6alkyl, carboxyC1-8alkyl, and C1-10alkylcarbonyl;
R, R1 and R8 are each independently
selected from the group consisting of hydrogen and C1-5alkyl;
R2 is
selected from the group consisting of aminoC2-5alkyl, guanidinoC2-5alkyl, C1-4alkylguanidinoC2-5alkyl, diC1-4alkylguanidino-C2-5alkyl, amidinoC2-5alkyl, C1-4alkylamidinoC2-5alkyl, diC1-4alkylamidinoC2-5alkyl, C1-3alkoxyC2-5alkyl, phenyl, substituted phenyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), benzyl, substituted benzyl (where the substituents on the benzyl are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), pyridyl, substituted pyridyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), pyridylC1-4alkyl, substituted pyridylC1-4alkyl (where the pyridine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), pyrimidylC1-4alkyl, substituted pynimidylC1-4alkyl (where the pyrimidine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), triazin-2-yl-C1-4alkyl, substituted triazin-2-yl-C1-4alkyl (where the triazine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), imidazoC1-4alkyl, substituted imidazoC1-4alkyl (where the imidazole substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), imidazolinylC1-4alkyl, N-amidinopiperazinyl-Nxe2x80x94C0-4alkyl, hydroxyC2-5alkyl, C1-5alkylaminoC2-5alkyl, C1-5dialkylaminoC2-5alkyl, N-amidinopiperidinylC1-4alkyl and 4-aminocyclohexylC0-2alkyl;
R3 and R4 are each independently
selected from the group consisting of hydrogen, C1-4alkyl, perfluoroC1-4alkyl, C1-4alkoxy, hydroxy, oxo, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyloxy, C1-4alkylcarbonylamino, aryl, substituted aryl (where the substituents on the aryl group are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyl, C1-4alkylcarbonylamino or C1-4alkoxycarbonyl), C1-4alkoxycarbonyl, aminosulfonyl. C1-4alkylaminosulfonyl, C1-4alkylsulfonylamino and N,N-di-C1-4alkylaminosulfonyl;
R5is
selected from the group consisting of hydrogen, C1-4alkyl and C1-4alkylcarbonyl;
R7is selected from the group consisting of hydrogen, C1-4alkyl C1-4alkylcarbonyl and aryl (where the substituents on the aryl group are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyl, C1-4alkylcarbonylamino or C1-4alkoxycarbonyl);
E is
an unsubstituted or substituted heterocycle selected from the group consisting of imidazolin-2-yl, imidazol-2-yl, oxazolin-2-yl, oxazol-2-yl, thiazolin-2-yl, thiazol-2-yl, thiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazin-3-yl, 1,3,5-triazin-2-yl, tetrazol-5-yl, isoxazol-3-yl, 1,2,3,4-oxatriazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 2-pyrazolin-3-yl, pyrazol-3-yl, pyrazin-2-yl, pyridazin-3-yl, pyrimidin-2-yl, 1H-indazole-3-yl, benzoxazol-2-yl, benzimidazol-2-yl, benzothiazol-2-yl, 4,5,6,7-tetrahydro-benzothiazol-2-yl, cinnolin-3-yl, phthalazin-1-yl, naphtho[2,1-d]thiazol-2-yl, naphtho[1,2-d]thiazol-2-yl, quinoxalin-2-yl, 4-oxoquinazolin-2-yl, quinazolin-2-yl, quinazolin-4-yl, purin-2-yl, purin-8-yl, pteridin-2-yl, pteridin-6-yl, oxazolo[4,5-b]pyridin-2-yl, oxazolo[5,4-b]pyridin-2-yl, thiazolo[4,5-b]pyridin-2-yl, thiazolo[5,4-b]pyridin-2-yl and thiazolo[5,4-c]pyridin-2-yl, wherein the substituents on the heterocycle are independently selected from C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, nitro, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkoxycarbonyl, phenylC1-4alkylaminocarbony, aryl, or substituted aryl where the substituents on the aryl are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, or C1-4alkoxycarbonyl;
provided that when
A is a polypeptide wherein the first amino acid is unsubstituted proline, and the second amino acid is selected from the group consisting of aspartic acid, aspartic acid4-C1-4alkyl ester, glutamic acid, glutamic acid-5-C1-4alkyl ester, phenylalanine, substituted phenylalanine (where the phenyl substituents are independently selected from one or more of, C1-4alkyl, perfluoroC1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy or C1-4alkoxycarbonyl), cyclohexylglycine, and cyclohexylalanine,
where the amino terminus of said second amino acid is monosubstituted with a member of the group consisting of C1-6alkyl, carboxyC1-8alkyl, and C1-10alkylcarbonyl;
then R2 is selected from the group consisting of substituted phenyl (where the substituents are independently selected from one or more of amidino, hydrazino, amidrazonyl), substituted benzyl (where the substituents on the benzyl are independently selected from one or more of amidino, hydrazino, amidrazonyl), pyridyl, substituted pyridyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), pyridylC1-4alkyl, substituted pyridylC1-4alkyl (where the pyridine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), pyrimidylC1-4alkyl, substituted pyrimidylC1-4alkyl (where the pyrimidine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), imidazoC1-4alkyl, triazin-2-yl-C1-4alkyl, substituted triazin-2-yl-C1-4alkyl (where the triazine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), substituted imidazoC1-4alkyl (where the imidazole substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), imidazolinylC1-4alkyl, and N-amidinopiperazinyl-Nxe2x80x94C0-4alkyl;
and pharmaceutically acceptable salts and prodrugs thereof.
In one embodiment of the invention is a compound of the formula (I) 
wherein
A, R, R1, R2, R3, R4, R5, R7, R8 and E are as defined above;
provided that when
A is a poly peptide comprised of two amino acids,
then R2 is selected from the group consisting of substituted phenyl (where the substituents are independently selected from one or more of amidino, hydrazino, amidrazonyl), substituted benzyl (where the substituents on the benzyl are independently selected from one or more of amidino, hydrazino, amidrazonyl), pyridyl, substituted pyridyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), pyridylC1-4alkyl, substituted pyridylC1-4alkyl (where the pyridine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), pyrimidylC1-4alkyl, substituted pyrimidylC1-4alkyl (where the pyrimidine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), triazin-2-yl-C1-4alkyl, substituted triazin-2-yl-C1-4alkyl (where the triazine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), imidazoC1-4alkyl, substituted imidazoC1-4alkyl (where the imidazole substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), imidazolinylC1-4alkyl, and N-amidinopiperazinyl-Nxe2x80x94C0-4alkyl;
and pharmaceutically acceptable salts and prodrugs thereof.
In a class of the invention is the compound of Formula (I) wherein
A is mono-substituted proline where the substituent is selected from hydroxy, halo or oxo;
R and R1 are both hydrogen;
R2 is guanidinoC2-5alkyl; and
E is benzothiazol-2-yl;
and pharmaceutically acceptable salts and prodrugs thereof.
Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. Illustrating the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
An example of the invention is a method of treating an inflammatory disorder (preferably, an immunomediated inflammatory disorder, most preferably a mast cell mediated inflammatory disorder) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
An illustration of the invention is a method of treating a disorder mediated by trypsin (e.g., pancreatitis) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
Also included in the invention is the use of any of the compounds described above for the preparation of a medicament for treating a condition selected from asthma, allergic rhinitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthrits, gouty arthritis, arthritic conditions in general (i.e., arthritis), peptic ulcers, ocular and vernal conjunctivitis, inflammatory bowel disease, Crohn""s disease, chronic obstructive pulmonary disease (COPD), urticaria, bullous pemphigoid, schieroderma, fibrosis, dermatitis, psoriasis, angioedema, eczematous dermatitis, anaphylaxis, hyperproliferative skin disease, inflammatory skin conditions, hepatic cirrhosis, glomerulonephritis, nephritis, vascular inflammation, atherosclerosis or restenosis in a subject in need thereof.
1. Synthetic Methods
The compounds of the invention may be prepared as illustrated according to the procedures and references set forth in detail in the following patents; U.S. Pat. Nos. 5,523,308, 5,164,371, WO 9619491 and WO 9748687. Additional procedures and references are described in the following citations: Bioorganic and Medicinal Chemistry Letters 1997, Vol. 7 pp. 1359-1364; Journal of Medicinal Chemistry 1996, Vol. 39, pp. 3039-3043; ibid. 1995, Vol. 38, pp. 76-85; ibid. 1994, Vol. 37, pp. 3492-3502. Preferred tryptase inhibitor compounds of the present invention may be prepared according to the detailed examples set forth herein.
Although the claimed compounds are useful as tryptase inhibitors, the preferred compounds of Formula (I) include: 
The particularly preferred xe2x80x9cAxe2x80x9ds are:
C3-8 cycloalkylcarbonyl (where the substituents on the C3-8 cycloalkyl group are independently one to two substituents selected from amido, C1-4alkylcarbonylamino or C1-4alkoxycarbonyl), substituted arylcarbonyl (where the substituents on the aryl group are independently one to two substituents selected from C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido), pyridylcarbonyl, substituted pyridylcarbonyl (where the substituents on the pyridine ring are independently one to three substituents selected from C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcabony, C1-4alkylcarbonylamino or C1-4alkoxycarbonyl), pyrrolocarbonyl, substituted pyrrolocarbonyl (where the substituents on the pyridine ring are independently one to three substituents selected from C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyl, C1-4alkylcarbonylamino or C1-4alkoxycarbonyl), 
xe2x80x83a D or L amino acid which is coupled at its carboxy terminus to the nitrogen depicted in formula (I) and is selected from the group consisting of pyrrole-2-carboxylic acid, dehydroproline, proline, substituted proline (where the the substituents on the proline are independently one to two substituents selected from C1-4alkyl, hydroxy, oxo, halo, amido, phenylalkyloxy, or C1-4alkoxy), pipecolinic acid,
where the amino terminus of said amino acid is connected to a member selected from the group consisting of C1-4alkoxycarbonyl, C1-8alkylcarbonyl, C1-4alkylsulfonyl, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, sulfonamido, arylcarbonyl, arylsulfonyl, and substituted arylsulfonyl (where the aryl substituents are independently one to two substituents selected from C1-4alkyl, or perfluoro C1-4alkyl).
Most preferably, A is substituted proline where the the substituents on the proline are independently one to two substituents selected from C1-4alkyl, hydroxy, oxo, halo, amido, phenylalkyloxy, or C1-4alkoxy.
The particularly preferred xe2x80x9cR1xe2x80x9ds are hydrogen and methyl; most preferably, hydrogen.
The particularly preferred xe2x80x9cR2xe2x80x9ds are selected from the group consisting of
aminoC2-5alkyl, guanidinoC2-5alkyl, amidinoC2-5alkyl, C1-5alkylaminoC2-5alkyl or C1-5dialkylaminoC2-5alkyl.
The particularly preferred xe2x80x9cExe2x80x9ds are heterocycles selected from the group consisting of unsubstituted or substituted
imidazol-2-yl, oxazolin-2-yl, oxazol-2-yl, thiazol-2-yl, benzoxazol-2-yl, benzimidazol-2-yl, benzothiazol-2-yl, 4,5,6,7-tetrahydro-benzothiazol-2-yl, 4-oxoquinazolin-2-yl, or quinazolin-2-yl, wherein the substituents on the heterocycle are independently one or two substituents selected from C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nxe2x80x94C1-4alkylamido, N,Nxe2x80x94C1-4dialkylamido, carboxy or C1-4alkoxycarbonyl.
2. Biological Methods
The compounds of this invention were tested for their ability to inhibit tryptase and chymase mediated hydrolysis via an in vitro enzyme assay.
Tryptase IC50 Method
The rate of increase in absorbance at 405 nM due to hydrolysis of synthetic chromogenic peptide substrates ([S]: 500 xcexcM N-p-Tosyl-GLY-PRO-LYS-pNA; Sigma T-6140) is measured in the presence and absence of inhibitors (I) with a microplate reader at 37xc2x0 C. The enzyme reaction is started by the addition of enzyme ([E]: 1.0 nM human Lung Tryptase; Cortex Biochem CP3033). Data is collected over a period of 30 min. and the initial rate of substrate hydrolysis (Vo (mOD/min)) is calculated. Inhibition is calculated by comparing to wells containing no inhibitor (vehicle) and IC50s are determined using a four parameter fit logistics model.
Trypsin IC50 Method
Inhibition of trypsin-catalyzed hydrolysis rates were measured using the same method as the tryptase procedure. Bovine type 1 trypsin (Sigma) and Spectrozyme(copyright) TRY (Cbo-Gly-D-Ala-Arg-pNA.AcOH, American Diagnostics) replaced their tryptase equivalents at concentrations of 3.2 U/ml trypsin and 1.0 mM Spectrozyme(copyright) TRY.
In addition, one of ordinary skill in the art can readily determine the utility of the compounds of formula (I) to act as tryptase inhibitors for treating asthma by using an in vivo sheep model which is described in Abraham et al. Amer. J. of Respir. and Crit. Care Med. 1996, 154, 649-654; and Clark et al. Amer. J. of Respir. and Crit. Care Med. 1995, 152, 2076-2083.
The terms used in describing the invention are commonly used and known to those skilled in the art. However, the terms that could have other meanings are defined. xe2x80x9cCBZxe2x80x9d refers to benzyloxycarbonyl. xe2x80x9cBOCxe2x80x9d refers to t-butoxycarbonyl and xe2x80x9cTsxe2x80x9d refers to toluenesulfonyl. xe2x80x9cDCCxe2x80x9d refers to 1,3-dicyclohexylcarbodiimide, xe2x80x9cDMAPxe2x80x9d refers to 4-Nxe2x80x2N-dimethylaminopyridine and xe2x80x9cHOBTxe2x80x9d refers to 1-hydroxybenzotriazole hydrate. xe2x80x9cDansylxe2x80x9d refers to 5-dimethylamino-1-naphthalenesulfonamide and xe2x80x9cFmocxe2x80x9d refers to N-(9-fluorenylmethoxycarbonyl). CAS#xe2x80x9d refers to Chemical Abstracts Service Registry Number. MS (ES) refers to positive ion electrospray mass spectroscopy and m/z refers to mass to charge ratio.
Typically the compounds of Formula I are isolated and used directly or as their pharmaceutically acceptable salts and prodrugs. Examples of such salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartatic, citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic and saccharic. Examples of such prodrugs include, but are not limited to, carbamates, N-acylamidines, N-acylguanidines, ketals, and enolethers.
The term xe2x80x9csubjectxe2x80x9d as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
As used herein, unless otherwise noted alkyl and alkoxy whether used alone or as part of a substituent group, include straight and branched chains having 1 to 8 carbon atoms, or any number within this range. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. Cycloalkyl groups contain 3 to 8 ring carbons and preferably 5 to 7 ring carbons. Similarly, alkenyl and alkynyl groups include straight and branched chain alkenes and alkynes having 1 to 8 carbon atoms, or any number within this range.
The term xe2x80x9carylxe2x80x9d as used herein refers to an aromatic group such as phenyl and naphthyl.
The term xe2x80x9cheteroarylxe2x80x9d as used herein represents a stable unsubstituted or substituted five or six membered monocyclic aromatic ring system or a nine or ten membered benzo-fused heteroaromatic ring system which consists of carbon atoms and from one to six heteroatoms (preferably, one to four heteroatoms) selected from N, O or S. The heteroaryl group may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of heteroaryl groups include, but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiophenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, purinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, indolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl or quinolinyl.
When a particular group (e.g., aryl, heteroaryl) is substituted, that group may have one or more substituents (preferably, one to five, more preferably, one to three, most preferably, one or two substituents) independently selected from the listed substituents.
The term xe2x80x9caralkylxe2x80x9d (e.g., arC1-4alkyl) means an alkyl group substituted with an aryl group (e.g., benzyl, phenylethyl). Similarly, the term xe2x80x9caralkoxyxe2x80x9d indicates an alkoxy group substituted with an aryl group (e.g., benzyloxy). The term xe2x80x9caminoalkylxe2x80x9d refers to an alkyl group substituted with an amino group (ie., -alkyl-NH2). The term xe2x80x9calkylaminoxe2x80x9d refers to an amino group substituted with an alkyl group (i.e., xe2x80x94NH-alkyl). The term xe2x80x9cdialkylaminoxe2x80x9d refers to an amino group which is disubstituted with alkyl groups wherein the alkyl groups can be the same or different (.e., xe2x80x94N-[alkyl]2).
The term xe2x80x9camidoxe2x80x9d refers to xe2x80x94C(O)xe2x80x94NH2. N-Alkylamido and N,N-dialkylamido refer to xe2x80x94C(O)xe2x80x94NH-alkyl and xe2x80x94C(O)xe2x80x94N(alkyl)2, respectively. Similarly, sulfoxamido refers to xe2x80x94SO2xe2x80x94NH2.
The term xe2x80x9camidrazonylxe2x80x9d as used herein refers to xe2x80x94C(xe2x95x90NH)NHxe2x80x94NH2 or xe2x80x94C(NH2)xe2x95x90Nxe2x80x94NH2, preferably, xe2x80x94C(xe2x95x90NH)NHxe2x80x94NH2.
The term xe2x80x9cacylxe2x80x9d as used herein means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group.
The term xe2x80x9chaloxe2x80x9d refers to a halogen and shall include iodine, bromine, chlorine and fluorine.
The term xe2x80x9coxoxe2x80x9d refers to xe2x95x90O.
Whenever the term xe2x80x9calkylxe2x80x9d or xe2x80x9carylxe2x80x9d or either of their prefix roots appear in a name of a substituent (e.g., aralkyl, dialkylamino) it shall be interpreted as including those limitations given above for xe2x80x9calkylxe2x80x9d and xe2x80x9caryl.xe2x80x9d Designated numbers of carbon atoms (e.g., C1-C6) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques know in the art as well as those methods set forth herein.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
The compounds of formula (I) are useful for treating inflammatory disorders (preferably, immunomediated inflammatory disorders, most preferably, mast cell mediated inflammatory disorders). Examples of immunomediated inflammatory disorders for which the compounds of the present invention are useful include, but are not limited to, asthma, allergic rhinitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, arthritic conditions in general (i.e., arthritis), peptic ulcers, ocular and vernal conjunctivitis, inflammatory bowel disease, chronic obstructive pulmonary disease (xe2x80x9cCOPDxe2x80x9d; see Grashoff, W. F. et al., American Journal of Pathology, 151(6):1785-90, December 1997), Crohn""s disease, urticaria, bullous pemphigoid, schleroderma, fibrosis, dermatitis, psoriasis, angioedema, eczematous dermatitis, anaphylaxis, hyperproliferative skin disease, inflammatory skin conditions, hepatic cirrhosis, glomerulonephritis, nephritis, vascular inflammation, atherosclerosis or restenosis.
The compounds of the formula (I) have also been shown to be effective in causing skin depigmentation and therefore may be useful in the treatment and/or prevention of skin hyperpigmentation.
The compounds of the formula (I) also function as inhibitors of thrombin and factor Xa. Consequently, they may be useful for the treatment of thrombin and/or factor Xa mediated disorders, such as thrombosis.
The compounds can be administered by any conventional route including but not limited to; oral, intravenous, intraperitoneal, intramuscular, subcutaneous, intranasal, topical, inhalation, suppository, and dermal patch, where the preferred route is inhalation. Doses can range from about 0.001 to about 2000 mg/kg/day (preferably, about 0.001 to about 200 mg/kg/day) of inhibitor admixed with a suitable pharmaceutical carrier. Doses can be given in a bolus fashion or over a time period at about 0.001-2000 mg/kg/day ranging from several minutes to several days.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, via inhalation or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
Optimal dosages of the compounds of formula (I) to be administered for the treatment of or prevention of immunomediated inflammatory disorders may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
Therapeutic agents that may be useful for administration in combination with compounds of formula (I) include xcex2-adrenergic agonists (e.g. albuterol, terbutaline, formoterol, fenoterol, prenaline and the like) methylxanthines (e.g. caffeine, theophylline, aminophylline, theobromine, and the like) and corticosteroids (e.g. beclomethasome, triamcinolone, flurisolide, dexamethasone, hydrocortisone, prednisone and the like). In general, one of ordinary skill in the art, acting in reliance upon personal knowledge and the disclosure of this application, will be able to ascertain the amounts of these respective therapeutic agents and the amount of the compound of the formula (I) which should be administered to a subject to treat a given immunomediated inflammatory disease. A xe2x80x9ctherapeutically effective amount,xe2x80x9d when referring to a combination of two or more agents, means an amount of each of the combined agents which is effective in eliciting the desired biological or medical response. For example, the therapeutically effective amount of a composition comprising Compound 1 and albuterol would be the amount of Compound 1 and the amount of albuterol that, when taken together, have a combined effect which is therapeutically effective. In accordance with the methods of treatment of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term xe2x80x9cadministeringxe2x80x9d is to be interpreted accordingly.
Additionally, the method of treating immunomediated inflammatory disorders of the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds of formula (I) and a pharmaceutically acceptable carrier. The compositions for treating inflammatory cell mediated inflammatory disorders include oral, inhalant, intranasal, intravenous, suppository, sustained release formulations, and topical preparations as well as devices used to administer such preparations. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions. Compositions useful for topical administration include liquid forms, emulsions, suspensions, gels, creams, ointments and sprays. Compositions suitable for inhalation include aerosolized solutions, emulsions, suspensions and dry powders. Compositions useful for parenteral administration include sterile solutions, emulsions and suspensions.
The pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and compounding techniques. To prepare the pharmaceutical compositions of this invention, one or more compounds of formula (I) or salt thereof of the invention as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. Oral dosage forms may be elixers, syrups, capsules, caplets, pills, tablets and the like. Where the typical solid carrier is an inert substance such as lactose, starch, glucose, methyl cellulose, magnesium sterate, dicalcium phosphate, mannitol and the like; and typical liquid oral excipients include ethanol, glycerol, water and the like. All excipients may be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known to those skilled in the art of preparing dosage forms. Parenteral dosage forms may be prepared using water or another sterile carrier.